The present invention relates to a solution for spray drying comprising hypromellose acetate succinate and a method for producing a solid dispersion.
A method for producing a solid dispersion comprising the steps of: dissolving a mixed solution of a drug and a polymer in a solvent, and removing the solvent for precipitation, has recently attracted attentions as a pharmaceutical preparation technique.
For example, a solid dispersion obtained by spray-drying a poorly water-soluble drug and a polymer has improved bioavailability because solubility of the drug apparently shows a marked increase due to molecular dispersion of the drug in the polymer carrier where the drug is in amorphous form.
One of the polymers to be used for such a solid dispersion is a hypromellose acetate succinate (hereinafter also referred to as “HPMCAS”), which is a polymer obtained by introducing four substituents in total. Two substituents, a methoxy group (—OCH3) and a hydroxypropoxy group (—OC3H6OH), are introduced into a cellulose skeleton to form an ether structure and the other two substituents, an acetyl group (—COCH3) and a succinyl group (—COC2H4COOH) are introduced to form an ester structure.
The content of each substituent of HPMCAS is listed in the Japanese Pharmacopoeia 16th Edition (“Hypromellose Acetate Succinate”, Official Monographs, Supplement I of the Japanese Pharmacopoeia 16th Edition) and is shown below.
TABLE 1content (% by weight)molar substitution (MS)*1methoxy group12.0~28.0 0.73~2.83hydroxypropoxy group4.0~23.00.10~1.90acetyl group2.0~16.00.09~2.30succinyl group4.0~28.00.08~1.78*1The molar substitution means an average mole of each introduced substituent per glucose ring unit of cellulose.
As a solid dispersion comprising HPMCAS, for example, a spray-dried solid dispersion comprising a poorly soluble drug and HPMCAS (commercially available AS having a molar substitution of from 0.16 to 0.35) is known (see JP 11-116502A).
In addition, a method for producing a preparation comprising the step of spray-drying posaconazole, which is a poorly water-soluble drug, and HPMCAS (commercially available AS-MF and AS-MG having a molar substitution of from 0.15 to 0.34) is proposed (see JP 2011-516613T which is the Japanese phase publication of WO 2009/129301A). A method for producing a preparation comprising the step of spray-drying itraconazole, which is a poorly water-soluble drug, and HPMCAS (commercially available AS-HG having a molar substitution of from 0.15 to 0.34) is also proposed (see JP 2004-067606A).
Further, a method of spray-drying a solid dispersion comprising a poorly water-soluble drug and HPMCAS having a hydroxypropoxy molar substitution of 0.25, a succinyl molar substitution of 0.02 or more, an acetyl molar substitution of 0.65 or more, and a total molar substitution of acetyl and succinyl groups of 0.85 or more is further proposed (see JP 2008-501009T, which is the Japanese phase publication of WO 2005/115330A). A method for spray-drying a solid dispersion comprising HPMCAS having a hydroxypropoxy molar substitution of 0.21 or less, a methoxyl molar substitution of 1.45 or less and a total molar substitution of acetyl and succinyl groups of 1.25 or more is also proposed (see WO2011159626A).
HPMCAS having a hydroxypropoxy molar substitution of 0.26 or less, a weight-average molecular weight Mw of from 80000 to 350000 Da, turbidity of 41 NTU or less as a 1.5% by weight solution thereof in acetone, and a viscosity of 4.0 mPa·s or less as a 2.0% by weight alkali (0.43% by weight) solution thereof (see WO2014/031422A).